In FY2017 we have made progress in the following areas: 1) Following infection with many viral pathogens, the virus first encounters components of the innate immune system that generate inflammatory signals that can initially control the infection, but the adaptive immune response is critical in determining whether the infection is ultimately cleared or becomes chronic. Signaling through the Type I IFN receptor (IFN/R or IFNAR) expressed on CD8+ and CD4+ T cells is required for Teff expansion and survival. We previously demonstrated that IFNAR signaling promotes Treg function in autoimmunity. To dissect the functional role of IFNAR-signaling in Tregs during acute and chronic viral infection, we infected Treg-specific IFNAR deficient (IFNARfl/flxFoxp3YFP-Cre) mice with LCMV Armstrong and Clone-13. In both models, IFNARfl/flxFoxp3YFP-Cre mice Tregs expressed enhanced expression of Treg associated activation antigens. The enhanced activated phenotype was also seen when we compared the transcriptomes of IFNARfl/flxFoxp3YFP-Cre and wild type (WT) Tregs by RNA-Seq on day 25-post Clone-13 infection. LCMV-specific CD8+ T cells from IFNARfl/flxFoxp3YFP-Cre mice produced less antiviral IFN-gamma and TNF-alpha in both acute and chronic LCMV. In the chronic model, the numbers of anti-viral effector and memory CD8+ T cells were decreased in IFNARfl/flxFoxp3YFP-Cre mice and the effector CD4+ and CD8+ T cells exhibited a phenotype compatible with enhanced exhaustion. IFNARfl/flxFoxp3YFP-Cre mice cleared Armstrong infection normally, but had higher viral titers in sera, kidneys and lungs than WT mice during chronic infection. Thus, type I IFN signaling in Tregs is context-dependent, resulting in enhanced suppressor function in some models of autoimmunity, but decreased suppressor function in acute and chronic viral infection. 2. Multiple sclerosis is an inflammatory demyelinating autoimmune disorder affecting the central nervous system whose severity is reduced using immune suppressive drugs. Therapeutic intervention with interferon-beta reduces disease exacerbations and delays relapses. The receptor for type 1 interferon, IFNAR, is present on virtually all cell types making it difficult to dissect the mechanisms involved. Mice with a conditional deletion (cKO) of IFNAR in Treg cells (IFNARfl/flFoxp3cre) developed severe EAE with an earlier onset than control mice. The activation status and effector cytokine production of CD4+ and CD8+ T cells in the draining lymph nodes (dLN) was similar in WT and cKO mice during the priming phase. Treg activation and expansion were also similar in WT and cKO mice. However, we noted a substantial reduction of myeloid derived suppressor cells (MDSCs) in the dLN of cKO mice, while equivalent numbers of MDSCs were present in bone marrow and spleen of WT and cKO mice. IFNARfl/flLysMcre mice do not show a similar reduction in MDSC number indicating that the enhanced disease severity in the cKO mice is dependent on IFNAR signaling in Treg cells. CD4+ T cells from cKO mice were found to be defective in chemokine secretion suggesting that IFNAR signaling on Treg modulates the capacity of CD4+ T cells to secrete MDSC recruiting chemokines during the priming phase. While modulation of Treg number and function by MDSCs has been documented, this study is one of the first to demonstrate that Treg may modulate MDSC homing and raises the possibility of a novel role for Treg cells in regulating the kinetics of MDSC recruitment during inflammatory conditions.